Objective:The choice of chemotherapeutic regimen for triple-negative breast cancer(TNBC)remains controversial.Homologous recombination deficiency(HRD)has attracted increasing attention in informing chemotherapy treatm...Objective:The choice of chemotherapeutic regimen for triple-negative breast cancer(TNBC)remains controversial.Homologous recombination deficiency(HRD)has attracted increasing attention in informing chemotherapy treatment.This study was aimed at investigating the feasibility of HRD as a clinically actionable biomarker for platinum-containing and platinum-free therapy.Methods:Chinese patients with TNBC who received chemotherapy between May 1,2008 and March 31,2020 were retrospectively analyzed with a customized 3D-HRD panel.HRD positivity was defined by an HRD score≥30 or deleterious BRCA1/2 mutation.A total of 386 chemotherapy-treated patients with TNBC were screened from a surgical cohort(NCT01150513)and a metastatic cohort,and 189 patients with available clinical and tumor sequencing data were included.Results:In the entire cohort,49.2%(93/189)of patients were identified as HRD positive(40 with deleterious BRCA1/2 mutations and 53 with BRCA1/2 intact with an HRD score of≥30).In the first-line metastatic setting,platinum therapy was associated with longer median progression-free survival(mPFS)than platinum-free therapy[9.1 vs.3.0 months;hazard ratio(HR),0.43;95%confidence interval 0.22–0.84;P=0.01].Among HRD-positive patients,the mPFS was significantly longer in those treated with platinum rather than platinum-free therapy(13.6 vs.2.0 months;HR,0.11;P=0.001).Among patients administered a platinum-free regimen,HRD-negative patients showed a PFS significantly superior to that of HRD-positive patients(P=0.02;treatment-biomarker P-interaction=0.001).Similar results were observed in the BRCA1/2-intact subset.In the adjuvant setting,HRD-positive patients tended to benefit more from platinum chemotherapy than from platinum-free chemotherapy(P=0.05,P-interaction=0.02).Conclusions:HRD characterization may guide decision-making regarding the use of platinum treatment in patients with TNBC in both adjuvant and metastatic settings.展开更多
The study on the coupling relationship and hydrology mechanism between ecosystem and hydrological process in a basin has recently become the international research frontier in hydrology.Runoff separation is still an i...The study on the coupling relationship and hydrology mechanism between ecosystem and hydrological process in a basin has recently become the international research frontier in hydrology.Runoff separation is still an important subject and possibly cutting edge process in hydrology.This paper summarizes the progress of national and international research,and comments on the advantages and disadvantages of recent,diverse base flow separation methods.This paper also presents research on hydrological process and eco-hydrological function in different landscape zones,combining isotopic technology with hydrochemical methods.Based on the runoff separation of different water bodies,this paper probes into the coupling relationship and hydrology mechanism between ecosystem pattern and eco-hydrological process,and makes analysis on water conservation,regulation and storage mechanism,and eco-hydrological function in different landscape zones.This report also examines future trends in research on hydrological process and eco-hydrological function in mountainous areas.展开更多
Adult stem cell therapy holds great promise for treating decompensated liver cirrhosis on the basis of animal studies,despite uncertainty about its clinical therapeutic effcacy and unclear underlying mechanisms.Here,w...Adult stem cell therapy holds great promise for treating decompensated liver cirrhosis on the basis of animal studies,despite uncertainty about its clinical therapeutic effcacy and unclear underlying mechanisms.Here,we investigated the role of follistatinlike 1(FsTL1),a profibrotic and proinflammatory matricellular protein,in inflammation-related heterogeneity in stem cell therapy.Our results showed that a high level of circulating FSTL1 is significantly correlated with therapeutic response in patients with cirrhosis.FSTL1 facilitated MSC^(-)mediated early recruitment of Ly6C^(+)inflammatory macrophages within 24 h postinfusion,which Was essential for the empowerment of MSCs and subsequent Ly6C^(-)CX3CR1^(+)macrophage remodelling at 48 h postinfusion.Fstl1 deficiency abrogated early macrophage recruitment and effective Ly6C^(-)CX3CR1^(+)macrophage accumulation,resulting in the poor antifibrotic effect of MSCs in mice.Whereas,recombinant FSTL1 protein restored the therapeutic efficacy of MSCs in CCl_(4)-injured Fstl1^(+/-)mice.Mechanistically,host FSTL1 enhanced rapid recycling of CCR2 to the membrane via activation of the CD14/TLR4/NFkB/ATP6V1G2 axis,leading to early recruitment of Ly6C^(+)monocytes/macrophages.Taken together,our findings revealed that FSTL1 is a critical regulator of the fibrotic immune microenvironment and facilitates subsequent stem cell therapy.These data suggest that FSTL1 could serve as a predictive biomarker of stem cell therapy response in patients with liver cirrhosis.展开更多
Acute-on-chronic liver failure(ACLF)is a complex clinical syndrome characterized by high 28-day and 90-day mortality rates,ranging from 13%to 93%,resulting from the acute deterioration of liver function in patients wi...Acute-on-chronic liver failure(ACLF)is a complex clinical syndrome characterized by high 28-day and 90-day mortality rates,ranging from 13%to 93%,resulting from the acute deterioration of liver function in patients with chronic liver disease.Transplantation of umbilical cord-derived mesenchymal stem cells(UC-MSCs)at different cell dosages has been shown to improve hepatic function in patients with decompensated cirrhosis or ACLF.[1,2]Notably,most clinical studies to date have used freshly prepared MSCs.This trial aimed to evaluate the tolerability,safety,and efficiency of off-the-shelf UC-MSC products in patients with ACLF.展开更多
基金granted by Capital’s Funds for Health Improvement and Research(Grant No.2018-2-4023)the National Natural Science Foundation of China(Grant No.82001559)。
文摘Objective:The choice of chemotherapeutic regimen for triple-negative breast cancer(TNBC)remains controversial.Homologous recombination deficiency(HRD)has attracted increasing attention in informing chemotherapy treatment.This study was aimed at investigating the feasibility of HRD as a clinically actionable biomarker for platinum-containing and platinum-free therapy.Methods:Chinese patients with TNBC who received chemotherapy between May 1,2008 and March 31,2020 were retrospectively analyzed with a customized 3D-HRD panel.HRD positivity was defined by an HRD score≥30 or deleterious BRCA1/2 mutation.A total of 386 chemotherapy-treated patients with TNBC were screened from a surgical cohort(NCT01150513)and a metastatic cohort,and 189 patients with available clinical and tumor sequencing data were included.Results:In the entire cohort,49.2%(93/189)of patients were identified as HRD positive(40 with deleterious BRCA1/2 mutations and 53 with BRCA1/2 intact with an HRD score of≥30).In the first-line metastatic setting,platinum therapy was associated with longer median progression-free survival(mPFS)than platinum-free therapy[9.1 vs.3.0 months;hazard ratio(HR),0.43;95%confidence interval 0.22–0.84;P=0.01].Among HRD-positive patients,the mPFS was significantly longer in those treated with platinum rather than platinum-free therapy(13.6 vs.2.0 months;HR,0.11;P=0.001).Among patients administered a platinum-free regimen,HRD-negative patients showed a PFS significantly superior to that of HRD-positive patients(P=0.02;treatment-biomarker P-interaction=0.001).Similar results were observed in the BRCA1/2-intact subset.In the adjuvant setting,HRD-positive patients tended to benefit more from platinum chemotherapy than from platinum-free chemotherapy(P=0.05,P-interaction=0.02).Conclusions:HRD characterization may guide decision-making regarding the use of platinum treatment in patients with TNBC in both adjuvant and metastatic settings.
基金supported by the West Action Program of Chinese Academy of Sciences (KZCX2-XB2-04-03)the Chinese National Natural Science Fund (40801021)+1 种基金the West Light Foundation of West Doctor of CASthe China Postdoctoral Science Foundation (200801244, 20070420135)
文摘The study on the coupling relationship and hydrology mechanism between ecosystem and hydrological process in a basin has recently become the international research frontier in hydrology.Runoff separation is still an important subject and possibly cutting edge process in hydrology.This paper summarizes the progress of national and international research,and comments on the advantages and disadvantages of recent,diverse base flow separation methods.This paper also presents research on hydrological process and eco-hydrological function in different landscape zones,combining isotopic technology with hydrochemical methods.Based on the runoff separation of different water bodies,this paper probes into the coupling relationship and hydrology mechanism between ecosystem pattern and eco-hydrological process,and makes analysis on water conservation,regulation and storage mechanism,and eco-hydrological function in different landscape zones.This report also examines future trends in research on hydrological process and eco-hydrological function in mountainous areas.
基金supported by the National Key R&D Program of China 2020YFA0710803(to J.W.),2017YFA0105704(to Y.H.),2021YFC25007002024YFA1108500(to W.N.)+1 种基金the National Natural Science Foundation of China(NSFC)grants 81900570,82470638(to X.Z.),82270551(to Y.H.),82270616(to J.W.),81900502(to G.G.),82303155(T.L.),82372882(L.G.)and 82030001(to W.N.)the Key Research and Development Program of Shaanxi Province,China no.2021ZDLSF02-07(toY.H.).
文摘Adult stem cell therapy holds great promise for treating decompensated liver cirrhosis on the basis of animal studies,despite uncertainty about its clinical therapeutic effcacy and unclear underlying mechanisms.Here,we investigated the role of follistatinlike 1(FsTL1),a profibrotic and proinflammatory matricellular protein,in inflammation-related heterogeneity in stem cell therapy.Our results showed that a high level of circulating FSTL1 is significantly correlated with therapeutic response in patients with cirrhosis.FSTL1 facilitated MSC^(-)mediated early recruitment of Ly6C^(+)inflammatory macrophages within 24 h postinfusion,which Was essential for the empowerment of MSCs and subsequent Ly6C^(-)CX3CR1^(+)macrophage remodelling at 48 h postinfusion.Fstl1 deficiency abrogated early macrophage recruitment and effective Ly6C^(-)CX3CR1^(+)macrophage accumulation,resulting in the poor antifibrotic effect of MSCs in mice.Whereas,recombinant FSTL1 protein restored the therapeutic efficacy of MSCs in CCl_(4)-injured Fstl1^(+/-)mice.Mechanistically,host FSTL1 enhanced rapid recycling of CCR2 to the membrane via activation of the CD14/TLR4/NFkB/ATP6V1G2 axis,leading to early recruitment of Ly6C^(+)monocytes/macrophages.Taken together,our findings revealed that FSTL1 is a critical regulator of the fibrotic immune microenvironment and facilitates subsequent stem cell therapy.These data suggest that FSTL1 could serve as a predictive biomarker of stem cell therapy response in patients with liver cirrhosis.
基金supported by grants from the National Key Research and Development Program of China(No.2020YFA0710804)Key Research and Development Program of Shaanxi(No.2023ZDLSF-34)Clinical Research Project of Air Force Military Medical University(Nos.2021LC2105 and 2023LC2311).
文摘Acute-on-chronic liver failure(ACLF)is a complex clinical syndrome characterized by high 28-day and 90-day mortality rates,ranging from 13%to 93%,resulting from the acute deterioration of liver function in patients with chronic liver disease.Transplantation of umbilical cord-derived mesenchymal stem cells(UC-MSCs)at different cell dosages has been shown to improve hepatic function in patients with decompensated cirrhosis or ACLF.[1,2]Notably,most clinical studies to date have used freshly prepared MSCs.This trial aimed to evaluate the tolerability,safety,and efficiency of off-the-shelf UC-MSC products in patients with ACLF.
